Respiratory syncytial virus (RSV) leads to lower respiratory tract infections. Immunocompromised patients, premature infants, and children are particularly at risk to severe disease. RSV is the leading cause of viral death in infants. RSV treatments are focused on prevention from infection and improving respiration. Palivizumab is a humanized monoclonal antibody that can be given prophylactically. Palivizumab is not effective after RSV infection, and protection ends shortly after treatment stops. Vaccines are not currently available for RSV. Attenuated RSV vaccines candidates have failed because of suboptimal immunogenicity in infants and suboptimal stability that leads to genetic reversion towards undesirable wild-type sequences. See Teng, Infectious Disorders—Drug Targets, 2012, 12(2):129-3. Thus, there is a need to find an attenuated RSV vaccine that is appropriately immunogenic, sufficiently stable, and safe for use in infants.
Due to the redundancy of the genetic code, individual amino acids are encoded by multiple sequences of codons, sometimes referred to as synonymous codons. In different species, synonymous codons are used more or less frequently, sometimes referred to as codon bias. Genetic engineering of under-represented synonymous codons into the coding sequence of a gene has been shown to result in decreased rates of protein translation without a change in the amino acid sequence of the protein. Mueller et al. report virus attenuation by changes in codon bias. See, Science, 2008, 320:1784. See also WO/2008121992, WO/2006042156, Burns et al., J Virology, 2006, 80(7):3259 and Mueller et al., J Virology, 2006, 80(19):9687.
Luongo et al. report increased genetic and phenotypic stability of a live-attenuated respiratory syncytial virus vaccine candidate by reverse genetics. See J. Virol. 2012, 86(19):10792.
Dochow et al. report independent structural domains in paramyxovirus polymerase protein. J Biol Chem, 2012, 287:6878-91.
U.S. Pat. No. 8,580,270 reports RSV F polypeptide sequences. U.S. Pat. No. 7,951,384 reports that it contemplates a VLP RSV vaccine.
References cited herein are not an admission of prior art.